Nsight Barbara Nelsen on the business of science.

Filed under Microbiome

Microbiome Therapeutics (Part 2)

Last week’s New York Times article on “Sharing My Stool” was a touching story of a successful outcome using Fecal Microbiota Transplant (FMT) to treat a patient with severe ulcerative colitis.  Within a few days there were almost 200 comments in response to this story. 

Many of the comments were from people sharing their struggles battling GI disease or infections for years, with several of them finding success with FMT.  And while these individual stories are certainly interesting, what do we really know about when this procedure will be mostly helpful rather than often harmful? And what is the best path forward to ensure that this treatment is widely available for the patients who could benefit from it?


When is FMT useful?

 In an earlier blog here, we discussed some of the findings on the ability of the bacteria in our guts influence health and resolve disease.  In May the FDA regulatory agency CBER held a two-day workshop on developing a path for the use of FMT. Here is snapshot of the some of the discussion around disease treatment.


In Animals: Reviewed by Linda Mansfield of Michigan State

For sick animals, transfaunation (or FMT) is used routinely. It cures chronic indigestion in calves, and colic in horses which can cause death in foals.  Analysis of the microbes in healthy and sick foals shows significant differences in the bacterial gut populations in healthy foals versus those with colitis.  But while FMT from healthy animals resolves colic, probiotics makes foals sicker.  This is an important finding because it suggests that what is in the mix (a few specific bacterial strains versus a diverse ecosystem) and the route of administration (oral versus colon) significantly impacts the outcome.

Bottom line:  FMT using material from a healthy donor is highly successful in animals and in regular use today.


In Human Disease:     

For Recurrent C Difficile Infection

History and recent results using FMT show the clear value of fecal transplantation to resolve recurrent C. Difficile infection in more than 93% of patients with a single transplant reviewed earlier here. The clinical data is so convincing in fact that the ACG just released guidelines recommending FMT for the 3rd recurrence of infection.  The primary concern raised during the CBER workshop for use of FMT was safety of the donor stool and the need for proper screening to ensure there is no inadvertent transmission or other infectious agents during the process.

Bottom Line: FMT for C Difficile is logical, low tech, and highly effective. Use of an industrially manufactured stool created from appropriately screened donors, combined with a national registry for FMT was recommended.


For Inflammatory Bowl Disease (IBD)

Attempts to use FMT in patients with IBD, including Crohn’s Disease and ulcerative colitis, has shown a wide range of responses from disease improvement to disease worsening.  FMT treatment (by Dr. Coleen Kelly of Brown University) of nine patients suffering with both IDB and C Difficile resolved the C Difficile infection but not the IBD.

But in another study of 25 patients with IBD, patients were treated with colonoscopic infusion of stool, followed by squeeze enema of stool at home  every week for 8 weeks and then as needed for maintenance. There was a wide range of responses with the most improvement shown by those treated within short time of disease onset.

Finally, in two pediatric trials of IBD, Sachan Kunde at Helen ve Vos Children’s hospital showed 62 % remission and 72% reduction of symptoms using a five-day administration regimen. http://clinicaltrials.gov/ct2/show/NCT01560819

Bottom line:  The jury is still out. We need to be more selective regarding whom should be considered for this treatment, when, and what the treatment regimen should be.


For Leukemia and Bone Marrow Transplant (BMT) patients

Infection with vancomycin resistant enterococcus (VRE) and C. Difficile are significant problems for leukemia and BMT transplant patients. Through studying mouse models and patients pre and post-BMT, Eric Pamer of Sloan Kettering has found that protective bacteria in the gut prior to transplant increase a patient’s resistance to infection later. (http://www.ncbi.nlm.nih.gov/pubmed/23319552) Specifically, Bacteroidetes provides resistance to C Difficile, with 50% of patients without Bacteroidetes becoming infected post transplant.  Similarly, high levels of Barnsiella — a subgroup of Bacteroidetes — in the gut flora prior to transplant correlated with patients who did not get VRE infections.

Bottom line:  A gut microbiome with high levels of Bacteroidetes and Barnsiella provides protection from infections in BMT patients.  FMT pre- or post-BMT may be a useful therapeutic solution for these common and dangerous infections in this fragile patient population.


What is the best path forward?

We don’t know anything about how FMT works, yet we know it can be extremely effective in resolving C. Difficile infections and potentially other GI disorders.  And we know that replacing the microbiota in the context of the whole ecosystem may be more relevant and useful then just replacing one or two isolated microbes.

A commercially available product from healthy donor material with off-the shelf availability, a National registry for FMT, and more clinical studies to define the optimal route and frequency of administration for other indications is needed. Only then can an FMT be widely available and effective for those who could most benefit from it most.

Full transcripts from the workshop can be found here.